Supplementary Material for: Direct Interaction of α-Synuclein and AKT Regulates IGF-1 Signaling: Implication of Parkinson Disease

Genetic mutation of α-synuclein (α-SYN) is clearly verified as the causal factor of human and mouse Parkinson’s disease. However, biological function of α-SYN has not been clearly demonstrated until now. In this investigation, we reveal that α-SYN is a co-regulator of growth factor-induced AKT activation. Elimination of SYN reduces the IGF-1-mediated AKT activation. Similarly, mutant SYN suppresses the IGF-1-induced AKT activation. Wild-type SYN can interact with AKT and enhance the solubility and plasma localization of AKT in response to IGF-1, whereas mutant α-SYNs do not interact with AKT. In addition, elevated expression of SYN blocks the AKT activation. We also find that si-RNA against α-SYN abolished the protective effect of IGF-1 against DNA damage-induced apoptosis. Our result strongly indicates that Parkinson’s disease, induced by α-SYN mutation, is evoked by deregulation of the AKT-signaling cascade.

α-突触核蛋白（α-synuclein，α-SYN）的基因突变已被明确证实为人类及小鼠帕金森病的致病诱因。然而，截至目前，α-SYN的生物学功能仍未得到清晰阐释。本研究证实，α-SYN是生长因子诱导的蛋白激酶B（AKT）活化的共调节因子。敲除α-SYN会减弱胰岛素样生长因子1（insulin-like growth factor 1, IGF-1）介导的AKT活化；与之类似，突变型α-SYN会抑制IGF-1诱导的AKT活化。野生型α-SYN可与AKT结合，并在IGF-1刺激下增强AKT的可溶性及细胞膜定位能力，而突变型α-SYN则无法与AKT结合。此外，α-SYN的过表达会阻断AKT的活化过程。我们还发现，靶向α-SYN的小干扰RNA（small interfering RNA, siRNA）会消除IGF-1对DNA损伤诱导的细胞凋亡的保护作用。本研究结果有力表明，由α-SYN突变引发的帕金森病，是由AKT信号级联反应失调所介导的。